1. Field of the Invention
This invention relates to delta-like ligand 4 (Dll4), in particular, Dll4 antagonists, and therapeutic methods using the same for inhibiting Dll4-mediated blood vessel development or growth and for inhibiting tumor growth. Dll4 antagonists are especially useful for treating tumor growth in tumors that are unresponsive to other anti-tumor agents. In addition, the combination of a Dll4 antagonist and another inhibitor of angiogenesis, such as a VEGF antagonist, is particularly effective in treating cancer and tumors that are resistant to either agent alone, or other anti-tumor agents.
2. Description of Related Art
The Notch-signaling pathway is a system for cell-to-cell communication used by a wide range of eukaryotes for many biological processes, such as differentiation, proliferation, and homeostasis. Delta like 4 (Dll4) or delta-like ligand 4 (Dll4) (hereinafter “Dll4”) is a member of the Delta family of Notch ligands which exhibits highly selective expression by vascular endothelium (Shutter et al. (2000) Genes Develop. 14:1313-1318). Dll4 is a ligand for Notch receptors, including Notch1 (the nucleic acid and amino acid sequences for human Notch1 are shown in SEQ ID NOS:5-6, respectively) and Notch 4 (the nucleic acid and amino acid sequences for human Notch4 are shown in SEQ ID NOS:7-8, respectively). The nucleic acid and amino acid sequences for human and mouse Dll4 are shown in SEQ ID NOS:1-2 and SEQ ID NOS:3-4, respectively. Gene targeted Dll4 mice have been generated (Duarte et al. (2004) Genes & Dev. 18: doi: 10.1101/gad. 1239004; Krebs et al. (2004) Genes & Dev. 18: doi: 10.1101/gad. 1239204: Gale et al. (2004) Proc Natl Acad Sci USA 101:15949-15954).